Polyurethane and polyurea biomaterials for use in medical devices

ABSTRACT

A medical device comprising a biomaterial formed from a polymer comprising urethane groups, urea groups, or combinations thereof, and sacrificial moieties that preferentially oxidize relative to other moieties in the polymer.

This application is a divisional application of U.S. patent applicationSer. No. 08/846,337 filed Apr. 30, 1997 entitled "Polyurethane andPolyurea Biomaterials for Use in Medical Devices" to DiDomenico et al.

FIELD OF THE INVENTION

This invention relates to medical devices that include polyurethane andpolyurea biomaterials, particularly elastomers, containing sacrificialmoieties (e.g., sulfur-containing moieties) that preferentially oxidizerelative to other moieties in the polymer.

BACKGROUND OF THE INVENTION

The chemistry of polyurethanes and polyureas is extensive and welldeveloped. Typically, polyurethanes and polyureas are made by a processin which a polyisocyanate is reacted with a molecule having at least twohydrogen atoms reactive with the polyisocyanate, such as a polyol orpolyamine. The resulting polymer can be further reacted with a chainextender, such as a diol or diamine, for example. The polyol orpolyamine can be a polyester, polyether, or polycarbonate polyol orpolyamine, for example.

Polyurethanes and polyureas can be tailored to produce a range ofproducts from soft and flexible to hard and rigid. They can be extruded,injection molded, compression molded, and solution spun, for example.Thus, polyurethanes and polyureas, particularly polyurethanes, areimportant biomedical polymers, and are used in implantable devices suchas artificial hearts, cardiovascular catheters, pacemaker leadinsulation, etc.

Commercially available polyurethanes used for implantable applicationsinclude BIOMER segmented polyurethanes, manufactured by Ethicon, Inc.,of Sommerville. N.J., PELLETHANE segmented polyurethanes, sold by DowChemical, Midland, Mich., and TECOFLEX segmented polyurethanes sold byThermedics, Inc., Woburn, Mass. These polyurethanes and others aredescribed in the article "Biomedical Uses of Polyurethanes," by Coury etal., in Advances in Urethane Science and Technology, 9, 130-168, editedby Kurt C. Frisch and Daniel Klempner, Technomic Publishing Co.,Lancaster, Pa. (1984). Typically, polyether polyurethanes exhibit morebiostability than polyester polyurethanes, and are therefore generallypreferred biopolymers.

Polyether polyurethane elastomers, such as PELLETHANE 2363-80A (P80A)and 2363-55D (P55D), which are believed to be prepared frompolytetramethylene ether glycol (PTMEG) and methylenebis(diisocyanatobenzene) (MDI) extended with butane diol (BDO), arewidely used for implantable cardiac pacing leads. Pacing leads areinsulated wires with electrodes that carry stimuli to tissues andbiologic signals back to implanted pulse generators. The use ofpolyether polyurethane elastomers as insulation on such leads hasprovided significant advantage over silicone rubber, primarily becauseof the higher tensile strength and elastic modulus of the polyurethanes.

There is some problem, however, with stress cracking of polyetherpolyurethane insulation, which can cause failure. Polyetherpolyurethanes are susceptible to oxidation in the body, particularly inareas that are under stress. When oxidized, polyether polyurethaneelastomers lose strength and form cracks, which eventually breach theinsulation. This, thereby, allows bodily fluids to enter the lead andform a short between the lead wire and the implantable pulse generator(IPG). It is believed that the ether linkages degrade, perhaps due tometal ion catalyzed oxidative attack at stress points in the material.

One approach to solving this problem has been to coat the conductivewire of the lead. Another approach has been to add an antioxidant to thepolyurethane. Yet another approach has been to develop new polyurethanesthat are more resistant to oxidative attack. Such polyurethanes includeonly segments that are resistant to metal induced oxidation, such ashydrocarbon- and carbonate-containing segments. For example,polyurethanes that are substantially free of ether and ester linkageshave been developed. This includes the segmented aliphatic polyurethanesof U.S. Pat. No. 4,873,308 (Coury et al.). Although such materialsproduce more stable implantable devices than polyether polyurethanes,there is still a need for biostable polymers, particularly polyurethanessuitable for use as insulation on pacing leads.

SUMMARY OF THE INVENTION

The present invention relates to medical devices comprising abiomaterial formed from a polymer comprising urethane groups, ureagroups, or combinations thereof (i.e., polyurethanes, polyureas, orpolyurethane-ureas). Preferably, the polymer is a segmentedpolyurethane. The polymer also includes sacrificial moieties (preferablyin the polymer backbone) that preferentially oxidize relative to allother moieties in the polymer. These sacrificial moieties are presentupon initial formation of the polymer and oxidize upon contact with theenvironment or body, for example. Significantly, the oxidation of suchsacrificial moieties typically provides improved mechanical properties,such as increased tensile strength and/or increased modulus ofelasticity, relative to the polymer prior to oxidation. As used herein,"sacrificial moiety" refers to the atom(s) or functional group that hasthe lowest oxidation potential within the molecule. Such moieties arethe preferential sites for oxidation. Preferably, the sacrificial moietyis a sulfur- or phosphorus-containing moiety, more preferably, asulfur-containing moiety, which can be oxidized to form a functionalgroup that imparts stronger mechanical properties to the polymer. Morepreferably, the polymer includes at least about 1.0 weight percentsulfur or phosphorus, and most preferably, at least about 1.2 weightpercent sulfur or phosphorus (preferably, sulfur), based on the totalweight of the polymer. The polymer is also preferably substantially freeof ester linkages and more preferably, substantially free of ester andether linkages.

Preferably, the biomaterials of the present invention are used in apacing lead as the insulation. Thus, the present invention provides amedical electrical lead comprising: an elongated insulation sheathformed from a polymer comprising urethane groups, urea groups, orcombinations thereof, and sacrificial moieties (preferably in thepolymer backbone) that preferentially oxidize relative to all othermoieties in the polymer, as described above; an elongated conductor,located within the elongated insulation sheath; an electrode coupled toa distal end of the elongated conductor; and an electrical connectorcoupled to a proximal end of the elongated conductor.

The present invention also provides a medical device comprising abiomaterial formed from a segmented polymer comprising urethane groups,urea groups, or combinations thereof, wherein the polymer is preparedfrom isocyanate-containing compounds and compounds of the formula:

    Y--R.sup.1 --(--X--R--X--R.sup.1 --).sub.n --X--R.sup.2 --Y

wherein Y is either OH or NH₂, n=0-100 (preferably 0-10), X is S orP--R³, R¹ and R² are each independently straight, branched, or cyclicaliphatic groups (preferably alkyl groups), and R³ is an aliphatic,aromatic, or araliphatic group. These sulfur and phosphorus-containinggroups are the preferred sacrificial moieties that can be oxidized tofunctional groups that preferably provide enhanced mechanical propertiesto the polymer. For example, a sulfur atom or sulfide (--S--) can beoxidized to a sulfoxide or sulfoxy (--S(O)--) group (with an IR peak atabout 1030 cm⁻¹) and then to a sulfone (--SO₂ --) group (with an IR peakat 1125 cm⁻¹ upon oxidation). Sulfoxide- and sulfone-containing polymerstypically have a higher tensile strength and a higher modulus ofelasticity than similar polymers containing sulfide moieties.

Also provided is a medical device comprising a biomaterial formed from apolymer comprising alternating soft and hard segments linked by urethanegroups, urea groups, or combinations thereof, wherein: (a) the softsegments are of the formula (--O or --OCNH)--(R^(a) --U--R^(b) --U)_(y)--R^(a) --(O-- or NHCO--), wherein: (i) each R^(a) and R^(b) isindependently a hydrocarbon moiety that can include linear, branched,cyclic structures, or combinations thereof, having a molecular weight ofless than about 4000, wherein at least one R^(a) or R^(b) isnoncrystallizing in the polymer at ambient temperature; (ii) each U isindependently a urethane group or a urea group; and (iii) y is theaverage number of repeating units, which is about 1-1000; (b) the hardsegments are of the formula (--O or --OCNH)--(R^(c) --U--R^(d) --U)_(z)--W--(O-- or NHCO--), wherein: (i) each R^(c) and R^(d) is independentlya hydrocarbon moiety that can include linear, branched, cyclicstructures, or combinations thereof, having a molecular weight of lessthan about 1000, wherein at least one R^(c) or R^(d) is crystallizing inthe polymer at ambient temperature; (ii) each U is independently aurethane group or a urea group; and (iii) z is the average number ofrepeating units, which is about 1-1000; and (c) at least one of the softsegments or the hard segments includes a sulfur-containing or aphosphorus-containing moiety in the polymer backbone.

The present invention also provides a segmented polyurethane comprisingalternating soft and hard segments linked by urethane groups, ureagroups, or combinations thereof, and at least one of the soft segmentsor the hard segments includes a sulfur-containing or aphosphorus-containing moiety in the polymer backbone. The soft segmentsare of the formula (--O or --OCNH)--(R^(a) --U--R^(b) --U)_(y) --R^(a)--(O-- or NHCO--) wherein: each R^(a) and R^(b) is independently ahydrocarbon moiety that can include linear, branched, cyclic structures,or combinations thereof, having a molecular weight of less than about4000, wherein at least one R^(a) or R^(b) is noncrystallizing in thepolymer at ambient temperatures; each U is independently a urethanegroup or a urea group; and y is the average number of repeating units,which is about 1-1000. The hard segments are of the formula (--O or--OCNH)--(R^(c) --U--R^(d) --U)_(z) --R--(O-- or NHCO--) wherein: eachR^(c) and R^(d) is independently a hydrocarbon moiety that can includelinear, branched, cyclic structures, or combinations thereof, having amolecular weight of less than about 1000, wherein at least one R^(c) orR^(d) is crystallizing in the polymer at ambient temperature; each U isindependently a urethane group or a urea group; and z is the averagenumber of repeating units, which is about 1-1000.

The present invention further provides a method of making a medicaldevice comprising a biomaterial. The method includes: combining at leastone isocyanate-containing compound with at least one diol- ordiamine-containing compound to form the biomaterial comprising urethanegroups, urea groups, or combinations thereof, and sacrificial moietiesthat preferentially oxidize relative to all other moieties in thepolymer; and forming a medical device with the biomaterial.

The present invention also provides a method of using a medical devicecomprising a biomaterial. The method includes: providing a medicalelectrical lead comprising a biomaterial comprising urethane groups,urea groups, or combinations thereof, and sacrificial moieties thatpreferentially oxidize relative to all other moieties in the polymer;implanting the medical electrical lead into a vein or artery of amammal; electrically connecting a first end of the medical electricallead to implantable medical device; and electrically stimulating orsensing a second end of the lead.

As used herein, "ambient temperature" refers to typical roomtemperatures, e.g., about 17-25° C. A "crystallizing" material is onethat forms ordered domains (i.e., aligned molecules in a closely packedmatrix), as evidenced by Differential Scanning Calorimetry, without amechanical force being applied. A "strain crystallizing" material is onethat forms ordered domains when a strain or mechanical force is applied.A "crystalline" material is one that has an ordered packing. A"noncrystallizing" material is one that forms amorphous domains, andnonglassy domains in the polymer at ambient temperatures. A"noncrystalline" material is one that is amorphous and nonglassy. A"semicrystalline" material is one that has both amorphous domains andcrystalline domains.

As used herein, a "biomaterial" may be defined as a material that issubstantially insoluble in body fluids and tissues and that is designedand constructed to be placed in or onto the body or to contact fluid ortissue of the body. Ideally, a biomaterial will not induce undesirablereactions in the body such as blood clotting, tissue death, tumorformation, allergic reaction, foreign body reaction (rejection) orinflammatory reaction; will have the physical properties such asstrength, elasticity, permeability and flexibility required to functionfor the intended purpose; can be purified, fabricated and sterilizedeasily; and will substantially maintain its physical properties andfunction during the time that it remains implanted in or in contact withthe body. A "biostable" material is one that is not broken down by thebody, whereas a "biocompatible" material is one that is not rejected bythe body.

As used herein, a "medical device" may be defined as a device that hassurfaces that contact blood or other bodily fluids in the course oftheir operation, which fluids are subsequently used in patients. Thiscan include, for example, extracorporeal devices for use in surgery suchas blood oxygenators, blood pumps, blood sensors, tubing used to carryblood and the like which contact blood which is then returned to thepatient. This can also include endoprostheses implanted in blood contactin a human or animal body such as vascular grafts, stents, pacemakerleads, heart valves, and the like, that are implanted in blood vesselsor in the heart. This can also include devices for temporaryintravascular use such as catheters, guide wires, and the like which areplaced into the blood vessels or the heart for purposes of monitoring orrepair.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a plan view of a pacing lead according to the presentinvention.

FIG. 2 is a graph of the modulus of elasticity of a polymericbiomaterial of the present invention with time in an oxidizingenvironment.

FIG. 3 is a graph of the modulus of elasticity of an alternativepolymeric biomaterial of the present invention with time in an oxidizingenvironment.

FIG. 4 is an infrared spectrum of the polymeric biomaterial of FIG. 3 ofthe present invention with time in an oxidizing environment.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides polymers that include, upon initialformation, a sacrificial moiety susceptible to oxidation. Significantly,upon oxidation, the mechanical properties of the polymer generallyimprove compared to the polymer prior to oxidation. The sacrificialmoiety is incorporated into the matrix of the polymer and oxidized toform a functional group that typically imparts stronger properties,particularly higher tensile strength and modulus of elasticity, forexample, to the polymer. It is also believed that the oxidized moietymay provide additional hydrogen bonding interactions and crystallinityto the polymer, thereby contributing to the enhanced mechanicalproperties of the polymer. This improved strength occurs with time uponoxidation as a result of contact with the environment or body.Eventually, however, as with most polymers, these polymers willeventually degrade over extended periods of time in an oxidizingenvironment.

The polymers suitable for forming the biomaterials for use in themedical devices of the present invention are polyurethanes, polyureas,or polyurethane-ureas. These polymers can vary from hard and rigid tosoft and flexible. Preferably, the polymers are elastomers. An"elastomer" is a polymer that is typically capable of being stretched toapproximately twice its original length and retracting to approximatelyits original length upon release.

Preferably, the polymers are segmented (i.e., containing both hard andsoft domains) and are comprised substantially of alternating relativelysoft segments and relatively hard segments, although nonsegmentedpolymers are also within the scope of the present invention. Either thehard or the soft segments, or both, include a sacrificial moiety that ispreferentially oxidized relative to any other moiety (i.e., atom(s) orfunctional group) in the polymer. As used herein, a "hard" segment isone that has a relatively higher concentration of urethane or ureagroups and hence is either crystalline at ambient temperature oramorphous with a glass transition temperature above ambient temperature,and a "soft" segment is one that has a relatively low concentration ofurethane or urea groups and hence is amorphous with a glass transitiontemperature below ambient temperature. A crystalline moiety or segmentis one that adds considerable strength and higher modulus to thepolymer. Similarly, a noncrystalline moiety or segment is one that addsflexibility and lower modulus, but may add strength particularly if itundergoes strain crystallization, for example. The random or alternatingsoft and hard segments are linked by urethane and/or urea groups and thepolymers may be terminated by hydroxyl, amine, and/or isocyanate groups.

Although certain preferred polymers are described herein, the polymersused to form the biomaterials in the medical devices of the presentinvention can be a wide variety of polymers comprising urethane groups,urea groups, or combinations thereof. Examples of such polymers aredescribed in U.S. Pat. No. 4,191,818 (Illers et al.), U.S. Pat. No.4,521,582 (Joyert et al.), and U.S. Pat. No. 4,098,773 (Illers et al.).Such polymers are prepared from isocyanate-containing compounds, such aspolyisocyanates (preferably diisocyanates) and compounds having at leasttwo hydrogen atoms reactive with the isocyanate groups, such as polyolsand/or polyamines (preferably diols and/or diamines). Any of thesereactants can include a sacrificial moiety (preferably in the polymerbackbone) that is preferentially oxidized as described herein, althoughpreferably the sacrificial moiety is provided by the polyols and/orpolyamines, particularly diols and/or diamines (including the diols ordiamines of the dimer acid described below). The sacrificial moiety ispreferably nonionic, and also preferably in the polymer backbone.

The sacrificial moiety can be a sulfur-containing moiety, such asmonosulfides and polythioethers. It can also be a phosphorus-containingmoiety, such as isobutyl bis-hydroxypropyl phosphine. The presence ofthe sacrificial moiety, preferably the sulfur- or phosphorus-containingmoiety, and more preferably the sulfur-containing moiety, provides apolymer that is more resistant to oxidative degradation than thecorresponding polymer that does not contain the sacrificial moiety. Thispolymer is capable of improved strength properties (e.g., tensilestrength, modulus of elasticity, etc.) upon oxidation, particularlybecause these moieties are bound into the polymer matrix, and alsobecause they provide increased hydrogen bonding capability uponoxidation.

Preferably, the polymer includes at least about 1.0 weight percent ofthe oxidizable atom (e.g., sulfur or phosphorus) of the sacrificialmoiety, based on the total weight of the polymer. More preferably, thepolymer includes at least about 1.2 weight percent of the oxidizableatom, and even more preferably, at least about 1.4 weight percent of theoxidizable atom. Most preferably, the polymer includes at least about2.0 weight percent of the oxidizable atom. Preferably, the oxidizableatom of the sacrificial moiety is sulfur.

The presence of the sacrificial moieties provides an improvement inmechanical properties over time when the polymer is in an oxidizingatmosphere. Preferably, there is an increase of at least about 25% inthe modulus of elasticity, and more preferably, at least about 50%, uponoxidation of the polymer when compared to the polymer prior tooxidation. Eventually, however, upon even further oxidation, themechanical properties of the polymer can decrease as a result of polymerdegradation, as do similar polymers without the sacrificial moiety. Itwill be understood by one skilled in the art that the mechanicalproperties of many polymers can increase slightly upon initialoxidation, however, this is believed to occur as a result ofcrosslinking, which is typically the first step in degradation.

Preferably, both the hard and soft segments are themselves substantiallyether- and ester-free polyurethanes, polyureas, or combinations thereofHerein, a substantially ether-free polymer or segment thereof issubstantially free of R--O--R linkages (i.e., ether linkages containingan oxygen), and a substantially ester-free polymer or segment thereof issubstantially free of R(O)--O--R linkages (i.e., ester linkagescontaining only oxygen). This does not include thioethers (i.e., R--S--Rlinkages), for example.

A preferred source of a sacrificial sulfur- or phosphorus-containingmoiety is a compound of the formula (Formula I):

    Y--R.sup.1 --(--X--R.sup.2 --X--R.sup.1 --).sub.n --X--R.sup.2 --Y

wherein Y is either OH or NH₂, n=0-100 (preferably 0-10), X is S orP--R³, R¹ and R² are each independently straight, branched, or cyclicaliphatic groups (preferably having 2-22 carbon atoms, more preferably2-11 carbon atoms, and most preferably 2-8 carbon atoms), and R³ is analiphatic (including cycloaliphatic), aromatic, or araliphatic group(i.e., a combination of aliphatic and aromatic groups, includingaralkyls and alkaryls). Preferably, R¹ and R² groups are alkyls.Examples of suitable materials include thiodiethanol,3,3-thiodipropanol, 4,4'-thiodibutanol, 1,4-dithane-2,5-diol,3-ethylthio-1,2-propanediol, polytetramethylenethioether diol,isobutylhydroxypropylphosphine, 2,2'-thiodiethylamine,3,6-dithia-1,8-octanediol, isobutylhydroxymethylphosphine,isobutylaminopropylphosphine, phenylhydroxypropylphosphine, etc.(available from Aldrich Chemical Co., Inc., Milwaukee, Wis., and Cytec,West Paterson, N.J., for example).

It should be understood, however, that diols or diamines that do notcontain sulfur- or phosphorus-containing moieties can also be used, aslong as the resultant polyurethane includes at least some sulfur- and/orphosphorus-containing moieties either from diols or diamines or otherreactants. Also, other polyols and/or polyamines can be used, includingpolyester and polyether polyols, for example, although polyester polyolsare less preferred because they produce less biostable materials.Furthermore, the polyols and polyamines can be aliphatic (straight,branched, or cyclic aliphatic), araliphatic, and aromatic (includingheterocyclic). Examples of suitable materials include 1,10-decane diol,1,12-dodecane diol, 9-hydroxymethyl octadecanol, cyclohexane-1,4-diol,cyclohexane-1,4-bis(methanol), cyclohexane-1,2-bis(methanol), ethyleneglycol, propylene glycol, trimethylene glycol, 1,2-butylene glycol,1,3-butane diol, 1,4-butane diol, 1,5-pentane diol, 1,2-hexylene glycol,1,2-cyclohexane diol, 2-butene-1,4-diol, 1,6-hexane diol, diolderivative of dimer acid (DIMEROL), and so forth.

Suitable isocyanate-containing compounds for preparation ofpolyurethanes, polyureas, or mixtures thereof, are typically aliphatic,cycloaliphatic, araliphatic, aromatic, and heterocyclic polyisocyanates.In addition to the isocyanate groups they can include other functionalgroups such as biuret, urea, siloxane, etc., that are typically used inbiomaterials. Suitable examples of polyisocyanates include4,4'-diisocyanatodiphenyl methane (MDI), 4,4'-diisocyanatodicyclohexylmethane (HMDI), cyclohexane-1,4-diisocyanate,cyclohexane-1,2-diisocyanate, isophorone diisocyanate,hexamethylene-1,6-diisocyanate, tolylene diisocyanates, naphthylenediisocyanates, benzene-1,4-diisocyanate, xylene diisocyanates,diisocyanate derivative of dimer acid (DDI), and so forth.

In preferred segmented polymers, soft segments are preferably based uponnoncrystallizing hydrocarbon backbones such as dimer acid derivatives,linked by urethane and/or urea groups to short and/or medium chainlength hydrocarbon moieties. The dimer acids are described and discussedin the book The Dimer Acids edited by Edward C. Leonard, published byHumko Shefield Chemical (1975). Dimer acids are the reaction product ofa Diels-Alder addition or other coupling reaction of two aliphatic,unsaturated fatty acids, typically having 18 carbon atoms. Dimer acidstake the form of single or double ring structures or branched chainhydrocarbon structures, having a variety of structural formulas.

Preferably, the soft segments of polyurethanes according to the presentinvention consist of noncrystallizing hydrocarbon backbones such asdimer acid derivatives, alternating or randomly dispersed with short tomedium chain hydrocarbon moieties and linked to them by urethane and/orurea groups. The soft segments may be produced by reacting either a dioland/or diamine derivative of dimer acid or a dilsocyanate derivative ofdimer acid with short to medium chain diols, diamines, and/ordiisocyanates. Due to the commercial availability of dimer diisocyanate,it is anticipated that in most cases the first segments will befabricated using dimer diisocyanate and short to medium chain lengthdiols and/or diamine. However, reaction of diol and/or diaminederivatives of dimer acid with short to medium chain diisocyanates isalso considered appropriate.

Dimer diisocyanate is a readily commercially available product, in whichthe hydrocarbon backbones of dimer acid have two of their substituentgroups terminated in isocyanate groups rather than carboxylic acidgroups. For purposes of the present invention, it is believed desirableto secure as pure a supply of dimer diisocyanate as is possible, withonly very limited quantities of trimer, monomer, and other oligomers.The hydrocarbon backbones of dimer acid as well as trimethylhexamethylene diisocyanate and 1,8-/1,9-heptadecane diisocyanate arebelieved particularly advantageous for incorporation in the relativelysoft segments of a segmented polyurethane. Their variety of branched andcyclic isomers provide chemically stable hydrocarbon backbones withdesirable mechanical properties.

In addition to the hydrocarbon backbones of dimer diisocyanate or otherdimer acid derivatives, the soft segments of the polyurethanes of thepresent invention include one or more short to medium chain lengthhydrocarbon moieties derived from diols, diamines, and/or diisocyanateshaving a molecular weight of less than about 4000. Preferably, thesemoieties should be derived from medium chain diols, diamines, and/ordiisocyanates having a molecular weight of about 146-1000.

The medium chain diols or diamines should have a chain length of atleast about 8 carbon atoms (in addition to the S or P moiety) separatingthe hydroxyl or amine groups. Diols are generally preferred. Appropriatemedium chain diols are listed above. They also include diol derivativesof dimer acid. Other diols or diamines having generally linearhydrocarbon chain lengths of 8 or more carbons separating the hydroxylor amine groups (in addition to the S or P moiety) and havinghydrocarbon side chains are believed to be similarly advantageous.

In some embodiments, it is desirable to include short chain hydrocarbonmoieties in the relatively soft segment. These short hydrocarbonmoieties may be derived from short chain diols, diamines, and/ordiisocyanates having chain lengths of 2-6 carbons (in addition to the Sor P moiety) between the hydroxyl or amine groups. Again diols aregenerally preferred. Appropriate short chain diols are listed above. Ifa diol derivative of dimer acid such as dimerol is used to provide thedimer acid backbones, short chain diisocyanates can serve as the sourceof these short chain hydrocarbon moieties. In some embodiments,inclusion of such short chain hydrocarbon moieties, with or without asulfur or phosphorus moiety, appears to enhance mechanical propertieswithout unduly reducing flexibility.

The relatively hard segments of the polymers used in the medical devicesof the present invention are preferably fabricated from short to mediumchain diisocyanates and short to medium chain diols or diamines, all ofwhich preferably have molecular weights of less than about 1000.Appropriate short to medium chain diols, diamines, and diisocyanatesinclude straight chain, branched, and cyclic aliphatics, althougharomatics can also be used. Examples of diols and diamines useful inthese more rigid segments include both the short and medium chain diolsor diarnines discussed above.

In cases where the relatively softer segments are produced by reactinglow noncrystalline Tg isocyanates (i.e., having a Tg of below ambienttemperature), such as dimer diisocyanate, trimethylhexamethylenediisocyanate, 1,8-/1,9-heptadecane diisocyanate, with an excess of diolsof the types described above, the softer segments will have the generalformula --O--(R³ --OOCNH--D--NHCOO)_(m) --R³ --O-- wherein D signifies anoncrystallizing hydrocarbon moiety which can include linear, branched,cyclic structures, or combinations thereof, such as dimer acidderivative, trimethylhexamethylene, or 1,8-/1,9-heptadecane, and R³signifies a hydrocarbon moiety derived from a diol that does not raisethe Tg of the segment above ambient temperature, and is preferablystrain crystallizing. The "m" signifies the average number of repeatingunits, which is typically about 1-1000. Similarly, if an excess of anoncrystalline diol, such as dimer diol, trimethyl hexamethylene diol,10-hydroxymethyloctadecanol is reacted with diisocyanates to produce thefirst, relatively softer segments, the general formula would be--O--(D--OOCNH--R⁴ --NHCOO)_(n) --D--O-- wherein D signifies anoncrystallizing hydrocarbon moiety which can include linear, branched,cyclic structures, or combinations thereof, such as a dimer acidderivative, and R⁴ signifies a hydrocarbon moiety derived from adiisocyanate that does not raise the Tg of the segment above ambienttemperature and is preferably strain crystallizing. In addition to MDI,examples of such diisocyanates include toluene diisocyanate (TDI),1,6-hexamethylene diisocyanate (HDI), HMDI (dicyclohexylmethanediisocyanate), and isophorone diisocyanate (IPDI). The "n" signifies theaverage number of repeating units, which is typically about 1-1000.

If the softer segments are produced by combining diols with an excess ofnoncrystalline isocyanates, the general formula would be--OCNH--(D--NHCOO--R⁵ --OOCNH)_(o) --D--NHCO-- wherein D signifies anoncrystallizing hydrocarbon moiety which can include linear, branched,cyclic structures, or combinations thereof, and R⁵ signifies ahydrocarbon moiety derived from a diol that does not raise the Tg of thesegment above ambient temperature and is preferably straincrystallizing. The "o" signifies the average number of repeating units,which is typically about 1-1000. Similarly, if the softer segments areproduced by combining a diol derivative with an excess of diisocyanates,the general formula would be --OCNH--(R⁶ --NCHOO--D--OOCNH)_(p) --R⁶--NHCO-- wherein D signifies a noncrystallizing hydrocarbon moiety whichcan include linear, branched, cyclic structures of a diol, orcombinations thereof, and R⁶ signifies a hydrocarbon moiety derived froma diisocyanate that does not raise the Tg of the segment above ambienttemperature and is preferably strain crystallizing. The "p" signifiesthe average number of repeating units, which is typically about 1-1000.

If the softer segments are produced using an excess of diols, thegeneral formula for the harder segments would be --OCNH--(R⁷ --NCHOO--R⁸--OOCNH)_(q) --R⁷ --NHCO-- wherein R⁸ signifies a moiety derived from adiol, and R⁷ signifies a moiety derived from a diisocyanate of the typesdescribed above (e.g., MDI, TDI, HDI, HMDI, and IPDI). The "q" signifiesthe average number of repeating units, which is typically about 1-1000.If the softer segments were produced using an excess of diisocyanates,the general formula for the harder segments would be --O--(R⁷--OOCNH--R⁸ --NHCOO)_(q) --R⁷ --O wherein R⁷, R⁸, and q are as definedabove.

The softer segments may therefore be described by the more generalformula (--O or --OCNH)--(R^(a) --U--R^(b) --U)_(y) --R^(a) --(O-- orNHCO--). In this formula, each R^(a) and R^(b) is independently ahydrocarbon backbone having a molecular weight of less than about 1000,wherein at least one is a hydrocarbon backbone of a noncrystallizinghydrocarbon derivative, and U signifies a urethane group. The "y"signifies the average number of repeating units, which is typicallyabout 1-1000.

The harder segments may be described by the more general formula (--O or--OCNH)--(R^(c) --U--R^(d) --U)_(z) --R^(c) --(O-- or NHCO--). In thisformula, each R^(c) and R^(d) is independently a hydrocarbon moietyhaving a molecular weight of less than about 1000, wherein at least oneis crystallizing at ambient temperature, U signifies a urethane group.The "z" signifies the average number of repeating units, which istypically about 1-1000.

In the more general formula set forth above, the hydrocarbon moieties inthe softer segment should not be construed to be limited to a particularor single hydrocarbon moiety, but may include one or more differenthydrocarbon moieties. As discussed above, in some embodiments, a mix ofshort and medium chain hydrocarbon moieties is believed desirable. Withregard to R^(c) and R^(d), the choice of separate designators for theR^(c) and R^(d) hydrocarbon moieties should not be considered to requirethat they are differing hydrocarbon moieties, but is intended only toreflect the fact that one of R^(c) and R^(d) is derived from adiisocyanate and the other is derived from a diol.

Any of the R or D groups defined in these soft and hard polyurethanesegments can include the sacrificial moiety, particularly sulfur- andphosphorus-containing moieties. Preferably, however, the sacrificialmoiety is incorporated into the polymers using diols, such as2,2'-thiodiethanol, 3,6-dithia-1,8-octanediol, 1,4-dithiane-2,5-diol,4,4'-thiodibutanol, and bis-hydroxypropyl phosphine (available fromCytec Industries, Inc., West Peterson, N.J.), for example.

The polymers described herein may be isocyanate, hydroxyl, and/or aminoterminated depending on the stoichiometric amounts of monomers used.Slightly hydroxyl terminated polymers are preferred for long termstability of the mechanical properties and molecular weight of thepolymer. It appears equally beneficial to "end cap" isocyanateterminated polymers with a monoalcohol to enhance stability.

The polymers described herein may be prepared using a one- or two-stageprocess. In a one-stage process, all the reactants are blended togetherand allowed to polymerize in a random fashion. The two-stage processcomprises initially combining noncrystalline isocyanate with medium ormedium and short chain diols or amines in a ratio of NCO:OH (or NCO:NH₂)of about 1:2 to 4:5, and more preferably of about 2:3. For certain ofthe polymers, the stoichiometric ratio of the medium chain to shortchain diols and/or amines preferably is about 1:3 to 4:1. However,useful polymers may be produced using only medium chain or short chaindiols and/or amines in the first stage. The combined reactants of thefirst stage are allowed to react until substantially no isocyanatefunctional groups remain to produce a hydroxyl or amine terminatedprepolymer.

The second stage comprises the addition of short to medium chain diolsand/or amines and short to medium chain diisocyanates to the adductproduced by the first stage. Preferably, the excess of diisocyanates inthe second stage is about equal to the excess of diols and/or amines inthe first stage to provide a generally balanced polymer. The totalstoichiometric ratio of first stage to second stage reactants may beadjusted to obtain desired physical properties.

The polymers produced according to the examples outlined below have beenfound to demonstrate improved mechanical properties upon oxidation (atleast upon initial oxidation). In particular, polyurethanes preparedfrom dimer diisocyanate, 2,2'-thiodiethanol, 1,4-cyclohexane dimethanol,1,6-hexane diisocyanate have been tested and compared with the sameformulation that had been exposed to oxidants. The exposed formulationshowed an increase in strength over the nonexposed formulation (at leastupon initial oxidation). That is, although the polymers are oxidized,their mechanical properties are enhanced. As a result, polyurethanesproduced according to the present invention are believed to beparticularly appropriate for use in implantable devices and are believedto be substantially superior to presently available polyurethaneformulations.

An example of a medical device for which the polymers are particularlywell suited is a medical electrical lead, such as a cardiac pacing lead,a neurostimulation lead, leads employing electrical transducers, etc.Examples of such leads are disclosed, for example, in U.S. Pat. No.5,040,544 (Lessar et al.), U.S. Pat. No. 5,375,609 (Molacek et al.),U.S. Pat. No. 5,480,421 (Otten), and U.S. Pat. No. 5,238,006(Markowitz). An example of a cardiac pacing lead is shown in FIG. 1. Thepacing lead 10 includes a connector assembly at its proximal end,including a first conductive surface 12, a second conductive surface 14,and two insulative segments 16 and 18. Insulative segments 16 and 18 areeach provided with a plurality of sealing rings 20. Extending from theconnector assembly is an elongated lead body, including an outerinsulative sheath 22, which is formed from the polymers described above.Within insulative sheath 22 is located an elongated conductor (notshown), such as a quadrifilar, multiconductor coil, which is describedin U.S. Pat. No. 5,040,544 (Lessar et al.). Two of the conductors withinthe coil are coupled to conductive surface 12, and the other two arecoupled to conductive surface 14. At the distal end of the lead arelocated a ring electrode 24, coupled to two of the conductors, and a tipelectrode 26, coupled to the other two of the four conductors of thequadrifilar coil. Extending between ring electrode 24 and tip electrode26 is an additional insulative sheath 28. Such medical electrical leadscan be implanted into a vein or artery of a mammal and electricallyconnected to an implantable medical device.

The invention has been described with reference to various specific andpreferred embodiments and will be further described by reference to thefollowing detailed examples. It is understood, however, that there aremany extensions, variations, and modification on the basic theme of thepresent invention beyond that shown in the examples and detaileddescription, which are within the spirit and scope of the presentinvention.

EXAMPLES

Test Methods

At least 8 replicates of each of 16 polyurethane film samples were cutinto no less than 10 cm×2 cm rectangles. The unused films were storedunder nitrogen in the dark. Screw capped jars were prepared with enough12.5% hydrogen peroxide so that the eight 10 cm×2 cm samples would becompletely covered. The 8 replicates for each of the 16 formulationswere placed into a separate jar (16 jars total) and covered with a knownvolume of the peroxide solution. The 17th jar was set up as a controlwith no polyurethane samples but the same volume of peroxide solution.The 17 jars were placed in a 37° C. oven (in the dark) and the date andtime were noted.

The samples were rinsed with water and dried under vacuum for 24 hoursbefore testing. Samples of the 100% modified polymers were evaluated attwo weeks, four weeks, five weeks, six weeks, and eight weeks. Eachreplicate was analyzed using FTIR analysis using attenuated totalreflectance techniques (ATR), a Zinc Selenide (ZnSe) ATR crystal, andscanned at a 45° angle of incidence. The absorbance peak at 1030 cm⁻¹was used to measure the oxidation of the thiol group (R--S--R) to thesulfoxy (R--SO--R'). This peak can be masked, however, in the spectra ofcertain polymer formulations. The absorbance peak at 1125 cm⁻¹ was usedto measure the oxidation of the sulfoxy group to the sulfone (R--SO₂--R').

Tensile testing was performed using ASTM D1708 (microtensile). Themicrotensile dogbone shape was used to cut test samples from the films.An MTS Sintech Model 1/D tensile tester was used. Samples were grippedat 80 psi, using a gauge length of 0.876 inches. The crosshead speed was5 inches/minute. The elastic modulus (Young's modulus) and the ultimatetensile strength were measured.

Dynamic Mechanical Analysis (DMA) was performed on a Perkin ElmerDMA-7e. The films were tested in tension. Samples of uniform rectangularshape were measured for thickness and width prior to mounting. Atemperature scan was performed on samples in tension at 1 Hz from 150°C. to 130° C. at 4° C/minute using 120% tension control and 5 micrometeramplitude control. The elastic modulus (i.e., storage modulus or modulusof elasticity) was measured as a function of temperature. Forthiodiethanol-derivatized samples oxidized over various times over 8weeks, temperature scans were performed in compression at 1 Hz from -50°C. to 170° C. at 5° C/minute using 120% tension control.

Gel permeation chromatography (GPC) was performed using a Waters 150 CVwith a Refractive Index detector. The samples were dissolved indimethylacetamide (DMAC) and analyzed using a relative polystyrenecalibration. The conditions of the analyses were as follows: DMAC mobilephase; 0-8 ml/minute flow rate; HT4-HT3-HT2 column set; 70° C. column,sample, and detector temperatures.

Formulations of Antioxidant-Containing Polyurethanes

All reactions were performed in a nitrogen-purged drybox. All diols weredried prior to use by application of heat and vacuum. A polypropylenebeaker was typically used as the reaction vessel and reactions weremixed by hand using a polyacetal stirring rod. 2,2'-Thiodiethanol (TDE),1,4-butanediol (BDO), 1,4-cyclohexanedimethanol (CHDM),1,6-diisocyanatohexane (HDI), and 4,4'-disocyanatodiphenyl methane (MDI)were purchased from Aldrich Chemical Company (Milwaukee, Wis.) and usedas received. The diisocyanate derivative of dimer acid (DDI) waspurchased from Henkel Corporation (Chicago, Ill.) and used as received.The diol derivative of dimer acid (DIMEROL) was purchased from UnichemaInternational and used as received.

Control 1: The polyurethane (Formulation I) used as the standard ofcomparison for Examples 1-9 was formulated as follows: 27.04 g1,4-cyclohexanedimethanol, 5.63 g BDO, and 118.37 g of the diisocyanatederivative of dimer acid were combined in a polypropylene beaker andstirred thoroughly until combined. The mixture was placed in a 50° C.oven and stirred every 15 minutes until the mixture was homogeneous andno IR bands due to NCO appeared. BDO (9.01 g) was stirred in followedquickly by 25.23 g HDI. The mixture was stirred until set and cured in a100° C. oven for 24 hours.

Example 1

The polyurethane of Formulation I was modified by substituting one molepercent of the 1,4-butanediol with 2,2'-thiodiethanol in both the hardand soft segment as follows: 98.65 g 1,4-butanediol and 1.35 g2,2'-thiodiethanol were stirred together until combined. In a separatepolypropylene beaker, 27.04 g CHDM, 5.65 g of the BDO/TDE mixture, and118.37 g of the diisocyanate derivative of dimer acid were combined andstirred thoroughly. The mixture was placed in a 50° C. oven and stirredevery 15 minutes until the mixture was homogeneous and no IR bands dueto NCO appeared. The BDO/TDE mixture (9.04 g) was stirred into themixture, quickly followed by 25.23 g 1,6-diisocyanatohexane. Theresultant mixture was stirred until set and cured in a 100° C. oven for24 hours to produce a polymer with 0.028 weight percent sulfur.

Example 2

The polyurethane of Formulation I was modified by substituting five molepercent of the 1,4-butanediol with 2,2'-thiodiethanol in both the hardand soft segment as follows: 93.34 g 1,4-butanediol (BDO) and 6.66 g2,2'-thiodiethanol were stirred together until combined. In a separatepolypropylene beaker, 27.04 g 1,4-cyclohexanedimethanol (CHDM), 5.73 gof the BDO/TDE mixture, and 118.37 g of the diisocyanate derivative ofdimer acid were combined and stirred thoroughly. The mixture was placedin a 50° C. oven and stirred every 15 minutes until the mixture washomogeneous and no IR bands due to NCO appeared. The BDO/TDE mixture(9.17 g) was stirred into the mixture, quickly followed by 25.23 g1,6-diisocyanatohexane. The resultant mixture was stirred until set andcured in a 100° C. oven for 24 hours to produce a polymer with 0.140weight percent sulfur.

Example 3

The polyurethane of Formulation I was modified by substituting ten molepercent of the 1,4-butanediol with by 2,2'-thiodiethanol in both thehard and soft segment as follows: 86.91 g 1,4-butanediol and 13.09 g2,2'-thiodiethanol were stirred together until combined. In a separatepolypropylene beaker, 27.04 g CHDM, 5.83 g of the BDO/TDE mixture, and118.37 g of the diisocyanate derivative of dimer acid were combined andstirred thoroughly. The mixture was placed in a 50° C. oven and stirredevery 15 minutes until the mixture was homogeneous and no IR bands dueto NCO appeared. The BDO/TDE mixture (9.33 g) was stirred into themixture, quickly followed by 25.23 g 1,6-diisocyanatohexane. Theresultant mixture was stirred until set and cured in a 100° C. oven for24 hours to produce a polymer with 0.280 weight percent sulfur.

Example 4

The polyurethane of Formulation I was modified by substituting 25 molepercent of the 1,4-butanediol with 2,2'-thiodiethanol in both the hardand soft segment as follows: 68.87 g 1,4-butanediol and 31.13 g2,2'-thiodiethanol were stirred together until combined. In a separatepolypropylene beaker, 27.04 g CHDM, 6.13 g of the BDO/TDE mixture, and118.37 g of the diisocyanate derivative of dimer acid were combined andstirred thoroughly. The mixture was placed in a 50° C. oven and stirredevery 15 minutes until the mixture was homogeneous and no IR bands dueto NCO appeared. The BDO/TDE mixture (9.81 g) was stirred into themixture, quickly followed by 25.23 g 1,6-diisocyanatohexane. Theresultant mixture was stirred until set and cured in a 100° C. oven for24 hours to produce a polymer with 0.698 weight percent sulfur.

Example 5

The polyurethane of Formulation I was modified by substituting 50 molepercent of the 1,4-butanediol with 2,2'-thiodiethanol in both the hardand soft segment as follows: 42.44 g 1,4-butanediol and 57.56 g2,2'-thiodiethanol were stirred together until combined. In a separatepolypropylene beaker, 27.04 g CHDM, 6.63 g of the BDO/TDE mixture, and118.37 g of the diisocyanate derivative of dimer acid were combined andstirred thoroughly. The mixture was placed in a 50° C. oven and stirredevery 15 minutes until the mixture was homogeneous and no IR bands dueto NCO appeared. The BDO/TDE mixture (10.62 g) was stirred into themixture, quickly followed by 25.23 g 1,6-diisocyanatohexane. Theresultant mixture was stirred until set and cured in a 100° C. oven for24 hours to produce a polymer with 1.386 weight percent sulfur.

Example 6

The polyurethane of Formulation I was modified by substituting 75 molepercent of the 1,4-butanediol with 2,2'-thiodiethanol in both the hardand soft segment as follows: 19.73 g 1,4-butanediol and 80.27 g2,2'-thiodiethanol were stirred together until combined. In a separatepolypropylene beaker, 27.04 g CHDM, 7.14 g of the BDO/TDE mixture, and118.37 g of the diisocyanate derivative of dimer acid were combined andstirred thoroughly. The mixture was placed in a 50° C. oven and stirredevery 15 minutes until the mixture :was homogeneous and no IR bands dueto NCO appeared. The BDO/TDE mixture (11.42 g) was stirred into themixture, quickly followed by 25.23 g 1,6-diisocyanatohexane. Theresultant mixture was stirred until set and cured in a 100° C. oven for24 hours to produce a polymer with 2.065 weight percent sulfur.

Example 7

The polyurethane of Formulation I was modified by substituting all the1,4-butanediol with 2,2'-thiodiethanol in both the hard and soft segmentas follows: in a polypropylene beaker, 27.04 g CHDM, 7.64 g TDE, and118.37 g of the diisocyanate derivative of dimer acid were combined andstirred thoroughly. The mixture was placed in a 50° C. oven and stirredevery 15 minutes until the mixture was homogeneous and no IR bands dueto NCO appeared. An additional 12.22 g TDE were stirred into themixture, quickly followed by 25.23 g 1,6-diisocyanatohexane. The mixturewas stirred until set and cured in a 100° C. oven for 24 hours toproduce a polymer with 2.734 weight percent sulfur.

Example 8

The polyurethane of Formulation I was modified by substituting BDO with3,6-dithia-1,8-octanediol (available from Aldrich Chemical Company,Madison, Wis.) as follows: in a polypropylene beaker, 27.04 g CHDM,11.40 g 3,6-dithia-1,8-octanediol, and 118.37 g of the diisocyanatederivative of dimer acid were combined and stirred thoroughly. Themixture was placed in a 50° C. oven and stirred every 15 minutes untilthe mixture was homogeneous and no IR bands due to NCO appeared. Anadditional 18.23 g 3,6-dithia-1,8-octanediol were stirred into themixture, quickly followed by 25.23 g HDI. The mixture was stirred untilset and cured in a 100° C. oven for 24 hours.

Example 9

The polyurethane of Formulation I was modified by substituting BDO with4,4'-thiodibutanol as follows: in a polypropylene beaker, 27.04 g CHDM,11.15 g 4,4'-thiodibutanol (synthesized by reacting two moles of4-chloro-1-butanol with one mole of sodium sulfide under phase transferconditions, and then the product was distilled to give the pure4,4'-thidibutanol), and 118.37 g of the diisocyanate derivative of dimeracid were combined and stirred thoroughly. The mixture was placed in a50° C. oven and stirred every 15 minutes until the mixture washomogeneous and no IR bands due to NCO appeared. An additional 17.83 g4,4'-thiodibutanol were stirred into the mixture, quickly followed by25.23 g HDI. The mixture was stirred until set and cured in a 100° C.oven for 24 hours.

Control 2: The polyurethane (Formulation II) used as the standard ofcomparison for Examples 10-16 was formulated as follows: 11.36 gDIMEROL, 3.60 g BDO, and 23.67 g of DDI were combined in a polypropylenebeaker and stirred thoroughly until combined. The mixture was placed ina 50° C. oven and stirred every 15 minutes until the mixture washomogeneous and no IR bands due to NCO appeared. BDO (1.80 g) wasstirred in followed quickly by 25.10 g MDI and 34.08 g DIMEROL. Themixture was stirred until set and cured in a 100° C. oven for 24 hours.

Example 10

The polyurethane of Formulation II was modified by substituting one molepercent of the 1,4-butanediol with 2,2'-thiodiethanol in both the hardand soft segment as follows: 98.65 g BDO and 1.35 g TDE were stirredtogether until combined. In a separate polypropylene beaker, 11.36 gDIMEROL, 3.62 g of the BDO/TDE mixture, and 23.67 g of DDI were combinedand stirred thoroughly. The mixture was placed in a 50° C. oven andstirred every 15 minutes until the mixture was homogeneous and no IRbands due to NCO appeared. The BDO/TDE mixture (1.81 g) was stirred intothe mixture, quickly followed by 25.10 g MDI and 34.08 g DIMEROL. Theresultant mixture was stirred until set and cured in a 100° C. oven for24 hours to produce a polymer with 0.019 weight percent sulfur.

Example 11

The polyurethane of Formulation II was modified by substituting fivemole percent of the 1,4-butanediol with 2,2'-thiodiethanol in both thehard and soft segment as follows: 93.34 g BDO and 6.66 g TDE werestirred together until combined. In a separate polypropylene beaker,11.36 g DIMEROL, 3.67 g of the BDO/TDE mixture, and 23.67 g of DDI werecombined and stirred thoroughly. The mixture was placed in a 50° C. ovenand stirred every 15 minutes until the mixture was homogeneous and no IRbands due to NCO appeared. The BDO/TDE mixture (1.83 g) was stirred intothe mixture, quickly followed by 25.10 g MDI and 34.08 g DIMEROL. Theresultant mixture was stirred until set and cured in a 100° C. oven for24 hours to produce a polymer with 0.096 weight percent sulfur.

Example 12

The polyurethane of Formulation II was modified by substituting ten molepercent of the 1,4-butanediol with 2,2'-thiodiethanol in both the hardand soft segment as follows: 86.91 g BDO and 13.09 g TDE were stirredtogether until combined. In a separate polypropylene beaker, 11.36 gDIMEROL, 3.74 g of the BDO/TDE mixture, and 23.67 g of DDI were combinedand stirred thoroughly. The mixture was placed in a 50° C. oven andstirred every 15 minutes until the mixture was homogeneous and no IRbands due to NCO appeared. The BDO/TDE mixture (1.86 g) was stirred intothe mixture, quickly followed by 25.10 g MDI and 34.08 g DIMEROL. Theresultant mixture was stirred until set and cured in a 100° C. oven for24 hours to produce a polymer with 0.193 weight percent sulfur.

Example 13

The polyurethane of Formulation II was modified by substituting 25 molepercent of the 1,4-butanediol with 2,2'-thiodiethanol in both the hardand soft segment as follows: 68.87 g BDO and 31.13 g TDE were stirredtogether until combined. In a separate polypropylene beaker, 11.36 gDIMEROL, 3.93 g of the BDO/TDE mixture, and 23.67 g of DDI were combinedand stirred thoroughly. The mixture was placed in a 50° C. oven andstirred every 15 minutes until the mixture was homogeneous and no IRbands due to NCO appeared. The BDO/TDE mixture (1.96 g) was stirred intothe mixture, quickly followed by 25.10 g MDI and 34.08 g DIMEROL. Theresultant mixture was stirred until set and cured in a 100° C. oven for24 hours to produce a polymer with 0.480 weight percent sulfur.

Example 14

The polyurethane of Formulation II was modified by substituting 50 molepercent of the 1,4-butanediol with 2,2'-thiodiethanol in both the hardand soft segment as follows: 42.44 g BDO and 57.56 g TDE were stirredtogether until combined. In a separate polypropylene beaker, 11.36 gDIMEROL, 4.25 g of the BDO/TDE mixture, and 23.67 g of DDI were combinedand stirred thoroughly. The mixture was placed in a 50° C. oven andstirred every 15 minutes until the mixture was homogeneous and no IRbands due to NCO appeared. The BDO/TDE mixture (2.12 g) was stirred intothe mixture, quickly followed by 25.10 g MDI and 34.08 g DIMEROL. Theresultant mixture was stirred until set and cured in a 100° C. oven for24 hours to produce a polymer with 1.427 weight percent sulfur.

Example 15

The polyurethane of Formulation II was modified by substituting 75 molepercent of the 1,4-butanediol with 2,2'-thiodiethanol in both the hardand soft segment as follows: 19.73 g BDO and 80.27 g TDE were stirredtogether until combined. In a separate polypropylene beaker, 11.36 gDIMEROL, 4.57 g of the BDO/TDE mixture, and 23.67 g of DDI were combinedand stirred thoroughly. The mixture was placed in a 50° C. oven andstirred every 15 minutes until the mixture was homogeneous and no IRbands due to NCO appeared. The BDO/TDE mixture (2.28 g) was stirred intothe mixture, quickly followed by 25.10 g MDI and 34.08 g DIMEROL. Theresultant mixture was stirred until set and cured in a 100° C. oven for24 hours to produce a polymer with 1.427 weight percent sulfur.

Example 16

The polyurethane of Formulation II was modified by substituting all the1,4-butanediol with 2,2'-thiodiethanol in both the hard and soft segmentas follows: in a polypropylene beaker, 11.36 g DIMEROL, 4.89 g TDE, and23.67 g of DDI were combined and stirred thoroughly. The mixture wasplaced in a 50° C. oven and stirred every 15 minutes until the mixturewas homogeneous and no IR bands due to NCO appeared. An additional 2.44g TDE were stirred into the mixture, quickly followed by 25.10 g MDI and34.08 g DIMEROL. The mixture was stirred until set and cured in a 100°C. oven for 24 hours to produce a polymer with 1.893 weight percentsulfuir.

After cure, the polyurethanes were processed by freezing in liquidnitrogen, breaking into pieces, and drying in a vacuum oven at 60° C.for 48 hours. The polymers were pressed at 165° C. to give films0.020-0.025 inches thick. These films were annealed in a 60° C. oven for48 hours, and these annealed films were the source from which samplesfor the testing of tensile properties were cut.

Results

In the first study, Formulation II was modified with either 1% or 100%TDE and Formulation I was modified with 1% TDE. Samples were oxidizedfor 8 weeks. Tensile testing compared the oxidized samples to thecorresponding unoxidized controls (Table 1; n≧5). The Formulation IIwith 100% TDE sample increased in both ultimate tensile strength (becamestronger) and Young's modulus (became harder) after 8 weeks ofoxidation. This is an advantage, since oxidation typically weakenspolymers. There was little difference in the test values before andafter oxidation for both Formulations I and II containing only 1% TDE.

                  TABLE 1                                                         ______________________________________                                        Tensile Testing of Oxidized and Unoxidized                                    Formulations Containing TDE.                                                                       Ultimate                                                                      tensile    Young's                                       Formulation Oxidized strength, psi                                                                            modulus, psi                                  ______________________________________                                        II with 100% TDE                                                                          Y        3,530 ± 320                                                                            14,530 ± 1,620                                        N        2,840 ± 300                                                                           9,470 ± 990                                II with 1% TDE                                                                            Y        4,270 ± 260                                                                           3,550 ± 550                                            N        4,330 ± 380                                                                           3,900 ± 250                                I with 1% TDE                                                                             Y        4,100 ± 390                                                                           6,340 ± 250                                            N        3,890 ± 300                                                                           6,200 ± 380                                ______________________________________                                    

The FTIR analysis of the polymer film during oxidation was performedduring the second study to monitor the oxidation process. Formulation Iwas used to monitor the formation of sulfoxy groups (R--SO--R'). Thiscan be seen in the spectra at 1030 cm⁻¹ (FIG. 4). The subsequentoxidation of the sulfoxy group to the sulfone was also observed in thespectra of Formulation I. The shoulder peak at 1125 cm⁻¹ became morepronounced as the oxidation time increased but the sulfoxy peak began tolessen at around the four to five week time period. This suggests thatthe conversion of sulfoxy to sulfone was occurring. The region in thespectra which is indicative of the sulfoxy group is masked but theregion indicative of the sulfone is clear. The sulfone peak became morepronounced as oxidation progressed. There appeared to be no othernoticeable oxidation/degradation of the polymer based on the infrareddata.

In a subsequent study, Formulations I and II were prepared with either0, 1, 5, 10, 25, 50, 75, or 100% TDE to help determine the useful rangein TDE content. Film samples were oxidized and tested at 0, 2, 4, 6, and8 weeks. The mechanical properties were measured by DMA (n=1). FIG. 2and Table 2 show how the DMA storage modulus of the TDE-modifiedFormulation II varied with oxidation time. Compared to the modulusvalues before oxidation, only the formulations containing 75% or 100%TDE increased significantly in modulus with oxidation time, indicatingan increase in hardness.

                  TABLE 2                                                         ______________________________________                                        Effect of Oxidation on DMA Modulus of Elasticity for TDE-Modified             Formulation II.                                                               DMA Modulus of Elasticity (psi, at 23° C.)                             Oxidation                                                                             0%      1%     25%   50%   75%    100%                                (weeks) TDE     TDE    TDE   TDE   TDE    TDE                                 ______________________________________                                        0       7810    7700   8070  8380   7720   8910                               2       6970    6710   6900  7160  12000  12860                               4       6700    6600   5740  8200  12090  15520                               6       7510    6510   7330  9160  11960  12960                               8       7470    6430   8050  8650  10550  13580                               ______________________________________                                    

FIG. 3 and Table 3 show how the DMA storage modulus of the TDE-modifiedFormulation I varied with oxidation time. Compared to the modulus valuesbefore oxidation, the formulation containing 100% TDE increasedsignificantly in modulus and remained above its initial values withcontinued oxidation time. The formulation containing 75% TDE increasedsignificantly above its initial value by 6 weeks, but dropped to belowthe initial modulus value at 8 weeks. This is believed to be due tocontinued oxidation and perhaps the beginning stage of degradation.

                  TABLE 3                                                         ______________________________________                                        Effect of Oxidation on DMA Storage Modulus for TDE-Modified                   Formulation I.                                                                Oxidation                                                                            DMA Storage Modulus (psi, at 23° C.)                            (weeks)                                                                              0% TDE   25% TDE  50% TDE                                                                              75% TDE                                                                              100% TDE                               ______________________________________                                        0      3790     4550     5230   3810   5980                                   2      4840     5030     5130   5920   6660                                   4      4240     5530     6880   5620   9800                                   6      5560     5100     6440   8950   10520                                  8      5540     4310     2820   1680   7310                                   ______________________________________                                    

DMA temperature scans of the 100% TDE-modified Formulation II before andafter 8 week oxidation were taken. The glass transition temperature ofthe formulation was affected by the oxidation, as evidenced in the shiftin the peak in tan 5 to higher temperatures. The glass transition of the100% Formulation II was converted into two transitions after oxidation,the peaks shifting about 10° C. and 30° C. as compared to the transitionbefore oxidation (Table 4). The glass transition was one broad peakbefore oxidation but became more sharp, splitting into two more welldefined peaks after the 8 week oxidation. The glass transition ischaracteristic of the primary structure of the polymer, and it isactually reflected by the chemical structure of the polymerizedmonomers. These data support the chemical changing of the primarystructure of the polymer. The sulfide group in the unoxidized TDEmonomer units was thought to have oxidized to a sulfoxide and/or asulfone. Since two new tan δ peaks occurred after oxidation, they mayhave been due to oxidation of the TDE to TDE-sulfoxide and TDE-sulfone.It makes sense that the glass transition would increase upon oxidationsince a sulfoxide or a sulfone group are both more bulky than a sulfidegroup. A shift of the glass transition to a higher temperature will alsoresult in a shift of the modulus--temperature curve. This caused themodulus to be greater at ambient temperature after oxidation. This wouldbe beneficial because it would lead to harder, and possibly stronger,materials after oxidation.

                  TABLE 4                                                         ______________________________________                                        DMA Glass Transition Temperatures for Unoxidized                              and Oxidized 100% TDE-Modified Formulation II.                                Sample        tan δ peak (° C.)                                                            tan δ onset (° C.)                     ______________________________________                                        Not oxidized  32          -5                                                  Oxidized 8 weeks                                                                            41, 61      24, 55                                              ______________________________________                                    

The GPC analysis of the polymers was carried out and suggested a changein the molecular weight distribution of the oxidized polymers. Thesamples contained a primary peak indicative of the polymer'sdistribution. This remained fairly stable for similar samples as theoxidation time increased. That is, the peak molecular weight of theprimary peak was fairly constant going from 0 weeks (control) to the 8week time of polymer modified with like amounts of TDE. A difference inthe relative ratio of a higher molecular weight component as compared tothe primary peak as a function of oxidation was observed. The highermolecular weight peak increased in intensity relative to the primarypeak. This may suggest that the thiol modification and subsequentoxidation may increase the overall molecular weight distribution. Thepolymers also do not appear to have undergone noticeable degradationbased on the lack of lower molecular weight species in the chromatogramand the stability of the primary GPC peak.

The complete disclosure of all patents, patent documents, andpublications cited herein are incorporated by reference, as ifindividually incorporated. The foregoing detailed description andexamples have been given for clarity of understanding only. Nounnecessary limitations are to be understood therefrom. The invention isnot limited to the exact details shown and described, for variationsobvious to one skilled in the art will be included within the inventiondefined by the claims.

What is claimed is:
 1. A method of making a medical device comprising abiomaterial, the method comprising the steps of:(a) combining at leastone isocyanate-containing compound with at least one diol- ordiamine-containing compound to form the biomaterial, the biomaterialcomprising urethane groups, urea groups, or combinations thereof, andsacrificial moieties that preferentially oxidize relative to all othermoieties in the polymer; and (b) forming a medical device with thebiomaterial.
 2. The method of claim 1 wherein the biomaterial comprisesat least one sulfur-containing moiety, at least onephosphorus-containing moiety, or combinations thereof.
 3. The method ofclaim 1 wherein the medical device comprises an electrical lead.
 4. Themethod of claim 1 wherein the biomaterial comprises a segmentedpolyurethane.
 5. The method of claim 1 wherein the sacrificial moietiescomprise at least about 1.2 weight percent of an oxidizable element,based on the total weight of the polymer.